The embryonic heart is initially a relatively straight muscle-wrapped tube created by a pair of bilateral membranes that fold and fuse along the midline of the embryo. Soon after the first contractions, the heart tube normally bends and twists toward the right side of the embryo, eventually creating the basic form of the mature heart. Even relatively minor perturbations in these processes can lead to serious congenital heart defects. Thus, it is important to understand the mechanisms that drive and regulate heart formation and looping. This proposed research deals with the biomechanical mechanisms of cardiac morphogenesis from the initial formation of the heart tube through the critical first phase of looping called "c-looping," when the heart deforms into a c-shaped tube. The long-term goal is to determine the fundamental biomechanical principles that regulate early heart development. A multifaceted approach involving experiments and computational modeling will be used to address the following specific aims: (1) Develop computational models for formation and looping of the embryonic heart. Micro indentation tests and optical coherence tomography (OCT), respectively, will furnish mechanical and geometric parameters for the model. (2) Determine the role that mechanical stresses in the omphalomesenteric veins play in left-right looping directionality. (3) Determine biomechanical mechanisms involved in formation of the heart tube in the early embryo. (4) Determine fundamental biomechanical principles that regulate formation and c-looping of the embryonic heart. Mathematical rules for tissue construction will be determined by comparing experimental and numerical results. Ultimately, this work will aid researchers searching for the link between gene expression and cardiac morphology as they devise new approaches for preventing and treating congenital heart disease. In addition, the computational model created during the course of our research may someday lead to advanced models of the developing human heart, which is not amenable to direct experimental study.